Cartilage-Specific Overexpression of ERRγ Results in Chondrodysplasia and Reduced Chondrocyte Proliferation.

“To assess the effect of increased ERRγ activity on cartilage development in vivo, we generated two transgenic (Tg) lines overexpressing ERRγ2 via a chondrocyte-specific promoter; the two lines exhibited ∼3 and ∼5 fold increased ERRγ2 protein expression respectively in E14.5 Tg versus wild type (WT) limbs. On postnatal day seven (P7), we observed a 4-10% reduction in the size of the craniofacial, axial and appendicular skeletons in Tg versus WT mice. The reduction in bone length was already present at birth and did not appear to involve bones that are derived via intramembranous bone formation as the bones of the calvaria, clavicle, and the mandible developed normally. Histological analysis of P7 growth plates revealed a reduction in the length of the Tg versus WT growth plate, the majority of which was attributable to a reduced proliferative zone. The reduced proliferative zone paralleled a decrease in the number of Ki67-positive proliferating cells, with no significant change in apoptosis, and was accompanied by large cell-free swaths of cartilage matrix, which extended through multiple zones of the growth plate. We identified known chondrogenesis-associated genes with at least one predicted ERR binding site in their proximal promoters, as well as cell cycle regulators known to be regulated by ERRγ. Of the genes identified, Col2al, Agg, Pth1r, and Cdkn1b (p27) were significantly upregulated, suggesting that ERRγ2 negatively regulates chondrocyte proliferation and positively regulates matrix synthesis to coordinate growth plate height and organization. ”

” in a cartilage-specific ERα-deleted mouse, appendicular bones developed normally, but exposure to high levels of estrogen failed to reduce bone length as it did in wild type (WT) mice, indicating that ERα was required for the natural deceleration of bone growth that occurs in mice upon sexual maturity”

Ironically, ERR-lambda decreased FGFR3 expression despite reducing height.

“Overexpression of ERRγ2 in a cartilage-specific manner leads to dose-dependent abnormalities in the axial and appendicular skeletons due to alterations in Cdkn1b expression and chondrocyte proliferation as well as differentiation-maturation- matrix synthesis”<-This is despite that ERRy2 results in overexpression of many anabolic chondrogenic genes.  Thus, it only takes one misexpressed gene to ruin longitudinal bone growth.


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